Mayo Clinic College of Medicine
Department of Physiology and Biomedical Engineering

PI: Hai-Long Wang

This researcher used MSI resources for two projects during this period. The first used MD simulations to explore the transport of single cations through the channel of the muscle nicotinic acetylcholine receptor (nAChR). The overall results show that cation selective transport through the nAChR channel is governed by electrostatic interactions to achieve charge selectivity, but ion translocation relies on channel hydration, facilitated by a trans-membrane field, coupled with dynamic fluctuations of the channel structure. This work has special interest in computational biology because it reveals molecular requirements for ion translocation across a prototypical hydrophobic channel.

The second project investigated the initial coupling of agonist binding to channel gating of the nicotinic acetylcholine receptor (nAChR) using Targeted Molecular Dynamics(TMD) simulation. Following TMD to accelerate closure of the C-loops at the agonist binding sites, the region of the pore that passes through the cell membrane expands. To determine whether the structural changes in the pore result in ion conduction, the researcher used a coarse-grained ion conduction simulator, called BiologyBoltzmann Transporter Monte Carlo(BioMOCA) simulation, and applied it to two structural frames taken from before and after the TMD simulation. The simulated ion conductance approaches that obtained experimentally and recapitulates several known functional properties of the nAChR. Thus, closure of the C-loop triggers a structural change in the channel pore that is sufficient to account for the open channel current. This approach of applying BioMOCA in computational studies of ion channels can be used to uncover the binding to gating transduction mechanism and the structural bases for ion selection and translocation.

Future work will focus on two directions: to apply long time all-atom explicit MD simulations to study the channel protein dynamics during the time when ions traverse through the ion channel pore; and to apply the coarse-grained ion conduction simulator combined with virtual mutagenesis to study how charged amino acid side chains at the pore surface affect ion conductance.